Project Summary (Core 4) Whole genome sequencing is a specialized function requiring expertise, special instruments and facilities along with informatics capabilities. This function cannot be performed in individual laboratories. Whole genome sequencing is also evolving rapidly and constantly improving the read capabilities, number of samples per run and informatics capabilities. There is only limited number of facilities available worldwide with such capabilities to continue to innovate. Welcome Trust Sanger Institute (WTSI) is a leader in sequencing the human genome, contributing one third of all the sequences and has made numerous contributions to other large genomes, lead efforts to sequence pathogens and disease vectors and mouse RI strain genomes. WTSI is committed to continually appraising new sequencing technologies, using in-house testing wherever possible, and will use whatever future technology is most suitable and cost-effective for the applications demanded by the science pursued at the Institute. The purpose of Core D is to provide for comprehensive genomic sequence analyses by utilizing a state of the art `next generation' sequencing platform for both the sequencing of whole genome as well as all coding exons/miRNA genes and the identification and characterization of genome-wide rearrangements at base-pair resolution in samples detailed in Projects 1 , 2 and 4. We have also developed and standardized single cell or small cell number whole genome sequencing. To meet these goals, in Core D we will pursue the following specific aims: to perform whole genome sequencing to generate genome wide substitution, indel, CNA and rearrangement data and streamlined analysis pipeline from IFM/DFCI 2017 study samples (Sp Aim 1); and to generate a genome-wide rearrangement data at base-pair resolution from selected samples to explore genomic changes during MM evolution from diagnosis to relapse (Sp. Aim 2). The core will also utilize methods developed1 to make high efficiency libraries from minimal residual disease settings (100- 500 cells) for Project 4, to generate representative genome libraries from a few hundred cells. Further, the core will provide bioinformatics expertise in the management and analysis of data produced within the core to support the projects.